The long-term goal of this project is to characterize the molecular basis of protein homeostasis and its regulation, and to understand how and why the capacity of this system declines with aging leading to both loss and gain of function diseases. Specific Aim 1 of this project will be to characterize the protein homeostasis network that controls the balance between amyloidogenic light chain (LC) folding and secretion versus degradation by endoplasmic reticulum (ER) associated degradation (ERAD) pathways to understand the basis for the human disease amyloid LC amyloidosis (AL). A high throughput screening (HTS) application of biologicals (siRNA and cDNA) to cell lines secreting amyloidogenic LCs will allow us to do a genome wide screen to uncover new targets that will shift the balance towards degradation and away from secretion of misfolding prone LCs, a result that is predicted to have a substantial impact on this disease, and possibly even cure the disease. Specific Aim 2 will also use a HTS format to identify small molecules in chemical libraries that diminish secretion of amyloidogenic LCs in favor of ERAD and therefore lead to reduction of extracellular amyloid load in tissue. In both specific aims we will explore the general hypothesis that protein homeostasis networks keep these diseases in check when we are young, but that a failure of these components during aging can contribute to gain-of-function proteotoxicity and organ failure due to amyloid burden that exceeds the capacity of repair and degradation pathways. Accomplishing these two specific aims involves a strong 4-way collaboration amongst investigators who have a track record of effective interaction, and have strong and complimentary expertise to apply cell biological, chemical and mouse and worm model approaches to understand AL disease in response to the aging program. Project Narrative: This project describes a new high-throughput screening approach to identify small molecule compounds and pathways that affect the onset and pathology of human myeloma disease light chain amyloidosis (AL) during aging. Identification of these pathways and compounds will lead to critical new insights into pathophysiology and a possible cure for disease.